Summary Platelet interactions with immune cells ? both direct and indirect ? accelerate the pathogenesis of vascular inflammatory and infectious diseases. Stimulated platelets release numerous immune molecules that drive inflammation independent of any thrombotic functions. We have discovered a novel mechanism of platelet initiated innate immune cell responses; platelet derived Beta2 microglobulin (?2M) is an immune molecule that mediates a pro-inflammatory monocyte phenotype. Using our novel platelet specific ?2M-/- mice we have now found that platelets are a major source of plasma ?2M, and that platelet derived ?2M has direct pro-inflammatory effects. This leads us to propose a novel mechanistic link between platelets, plasma ?2M, and immune cell responses, particularly platelet driven monocyte pro-inflammatory responses. Hypothesis: ?2M is a novel platelet derived mediator of a pro-inflammatory monocyte phenotype. Specific Aim # 1. To demonstrate mechanisms of platelet mediated monocyte inflammatory phenotype in vitro. We will use in vitro cell based studies to show how platelet derived ?2M induces monocyte pro- inflammatory responses. Specific Aim # 2. To demonstrate how platelet-derived ?2M mediates monocyte responses and outcomes in an ischemic myocardial injury model. We will use our established myocardial infarction model to demonstrate the pathophysiologic mechanism of ?2M mediated ischemic tissue injury. This proposal will demonstrate novel mechanisms for platelet mediated monocyte activation that have direct impacts on major causes of morbidity and mortality worldwide. Results of our studies will influence the work of many other groups and research projects. This proposal consists of an ambitious set of studies that our research team is uniquely situated to pursue.